Numerical Solution of Nonlinear Pharmacokinetic Equations: Effects of Plasma Protein Binding on Drug Distribution and Elimination

• Published in: Journal of pharmaceutical sciences 1971-11, Vol.60 (11), p.1623-1628
• Main Authors: Coffey, John J., Bullock, Francis J., Schoenemann, Paul T.
• Format: Article
• Language: English
• Subjects: Aldosterone - metabolism; Binding site competition-drug-plasma; Binding site competition—drug‐plasma, two‐compartment model; Binding site competition−drug-plasma, two-compartment model; Binding Sites; Blood Proteins - metabolism; Drug-plasma protein binding-quantitation of nonlinear equations; Drug-plasma protein binding−quantitation of nonlinear equations; effect of plasma protein binding on drug distribution and elimination; Kinetics; Models, Biological; Pharmacokinetics-quantitation of nonlinear equations; Pharmacokinetics—quantitation of nonlinear equations, effect of plasma protein binding on drug distribution and elimination; Pharmacokinetics−quantitation of nonlinear equations, effect of plasma protein binding on drug distribution and elimination; Phenylbutazone - metabolism; Protein Binding - drug effects; Thyroxine - metabolism; Transcortin - metabolism; two-compartment model; Warfarin - metabolism
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600601106

Numerical methods are described for the solution of the differential equations arising from nonlinear binding of drugs to plasma proteins, assuming one- and two-compartment pharmacokinetic models. These numerical methods should be of general utility in studying multicompartment models. The application of these methods to several systems, both hypothetical and real, suggested that binding of drugs to plasma protein should cause detectable nonlinearity in the log C versus t plot only if doses are sufficiently high to approach saturation of binding sites or if the number of binding sites in plasma is small. The effect of competition for binding sites in plasma on drug concentrations in tissues was studied by assuming a two-compartment model. It appears that, unless the tissue distribution volume is quite small, competition for binding sites would not be expected to have a large effect.